tbuckley/cabot-search huggingface dataset:
Methodologic Concerns in Secondary Analysis of KEYNOTE-048—Reply
Authors: Yao Yu, Eric J. Sherman, Nancy Y. Lee
Journal: JAMA Oncology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Reimagining Cancer: Moving from the Cellular to the Tissue Level
Authors: Romano Demicheli, William J.M. Hrushesky
Journal: Cancer Research (2022)

The current universally accepted explanation of cancer origin and behavior, the somatic mutation theory, is cell-centered and rooted in perturbation of gene function independent of the external environmental context. However, tumors consist of various epithelial and stromal cell populations temporally and spatially organized into an integrated neoplastic community, and they can have properties similar to normal tissues. Accordingly, we review specific normal cellular and tissue traits and behaviors with adaptive temporal and spatial self-organization that result in ordered patterns and structures. A few recent theories have described these tissue-level cancer behaviors, invoking a conceptual shift from the cellular level and highlighting the need for methodologic approaches based on the analysis of complex systems. We propose extending the analytical approach of regulatory networks to the tissue level and introduce the concept of "cancer attractors." These concepts require reevaluation of cancer imaging and investigational approaches and challenge the traditional reductionist approach of cancer molecular biology.
An Aged/Autoimmune B-cell Program Defines the Early Transformation of Extranodal Lymphomas
Authors: Leandro Venturutti, Martin A. Rivas, Benedikt W. Pelzer, Ruth Flümann, Julia Hansen, Ioannis Karagiannidis, Min Xia, Dylan R. McNally, Yusuke Isshiki, Andrew Lytle, Matt Teater, Christopher R. Chin, Cem Meydan, Gero Knittel, Edd Ricker, Christopher E. Mason, Xiaofei Ye, Qiang Pan-Hammarström, Christian Steidl, David W. Scott, Hans Christian Reinhardt, Alessandra B. Pernis, Wendy Béguelin, Ari M. Melnick
Journal: Cancer Discovery (2022)

A third of patients with diffuse large B-cell lymphoma (DLBCL) present with extranodal dissemination, which is associated with inferior clinical outcomes. MYD88L265P is a hallmark extranodal DLBCL mutation that supports lymphoma proliferation. Yet extranodal lymphomagenesis and the role of MYD88L265P in transformation remain mostly unknown. Here, we show that B cells expressing Myd88L252P (MYD88L265P murine equivalent) activate, proliferate, and differentiate with minimal T-cell costimulation. Additionally, Myd88L252P skewed B cells toward memory fate. Unexpectedly, the transcriptional and phenotypic profiles of B cells expressing Myd88L252P, or other extranodal lymphoma founder mutations, resembled those of CD11c+T-BET+ aged/autoimmune memory B cells (AiBC). AiBC-like cells progressively accumulated in animals prone to develop lymphomas, and ablation of T-BET, the AiBC master regulator, stripped mouse and human mutant B cells of their competitive fitness. By identifying a phenotypically defined prospective lymphoma precursor population and its dependencies, our findings pave the way for the early detection of premalignant states and targeted prophylactic interventions in high-risk patients. Extranodal lymphomas feature a very poor prognosis. The identification of phenotypically distinguishable prospective precursor cells represents a milestone in the pursuit of earlier diagnosis, patient stratification, and prophylactic interventions. Conceptually, we found that extranodal lymphomas and autoimmune disorders harness overlapping pathogenic trajectories, suggesting these B-cell disorders develop and evolve within a spectrum. See related commentary by Leveille et al. (Blood Cancer Discov 2023;4:8-11). This article is highlighted in the In This Issue feature, p. 1.
<i>Lactiplantibacillus plantarum</i> 299v supplementation modulates β-cell ER stress and antioxidative defense pathways and prevents type 1 diabetes in gluten-free BioBreeding rats
Authors: Pinar Sargin, Mark F. Roethle, Shuang Jia, Tarun Pant, Ashley E. Ciecko, Samantha N. Atkinson, Nita H. Salzman, Ru-Jeng Teng, Yi-Guang Chen, Susanne M. Cabrera, Martin J. Hessner
Journal: Gut Microbes (2022)

The increasing incidence of Type 1 diabetes has coincided with the emergence of the low-fiber, high-gluten Western diet and other environmental factors linked to dysbiosis. Since Lactiplantibacillus plantarum 299 v (Lp299v) supplementation improves gut barrier function and reduces systemic inflammation, we studied its effects in spontaneously diabetic DRlyp/lyp rats provided a normal cereal diet (ND) or a gluten-free hydrolyzed casein diet (HCD). All rats provided ND developed diabetes (62.5±7.7 days); combining ND with Lp299v did not improve survival. Diabetes was delayed by HCD (72.2±9.4 days, p = .01) and further delayed by HCD+Lp299v (84.9±14.3 days, p < .001). HCD+Lp299v pups exhibited increased plasma propionate and butyrate levels, which correlated with enriched fecal Bifidobacteriaceae and Clostridiales taxa. Islet transcriptomic and histologic analyses at 40-days of age revealed that rats fed HCD expressed an autophagy profile, while those provided HCD+Lp299v expressed ER-associated protein degradation (ERAD) and antioxidative defense pathways, including Nrf2. Exposing insulinoma cells to propionate and butyrate promoted the antioxidative defense response but did not recapitulate the HCD+Lp299v islet ERAD transcriptomic profile. Here, both diet and microbiota influenced diabetes susceptibility. Moreover, Lp299v supplement modulated antioxidative defense and ER stress responses in β-cells, potentially offering a new therapeutic direction to thwart diabetes progression and preserve insulin secretion.
N-myc–Mediated Translation Control Is a Therapeutic Vulnerability in Medulloblastoma
Authors: Duygu Kuzuoglu-Ozturk, Ozlem Aksoy, Christin Schmidt, Robin Lea, Jon D. Larson, Ryan R.L. Phelps, Nicole Nasholm, Megan Holt, Adrian Contreras, Miller Huang, Shannon Wong-Michalak, Hao Shao, Robert Wechsler-Reya, Joanna J. Phillips, Jason E. Gestwicki, Davide Ruggero, William A. Weiss
Journal: Cancer Research (2022)

Abstract Deregulation of neuroblastoma-derived myc (N-myc) is a leading cause of malignant brain tumors in children. To target N-myc-driven medulloblastoma, most research has focused on identifying genomic alterations or on the analysis of the medulloblastoma transcriptome. Here, we have broadly characterized the translatome of medulloblastoma and shown that N-myc unexpectedly drives selective translation of transcripts that promote protein homeostasis. Cancer cells are constantly exposed to proteotoxic stress associated with alterations in protein production or folding. It remains poorly understood how cancers cope with proteotoxic stress to promote their growth. Here, our data revealed that N-myc regulates the expression of specific components (∼5%) of the protein folding machinery at the translational level through the major cap binding protein, eukaryotic initiation factor eIF4E. Reducing eIF4E levels in mouse models of medulloblastoma blocked tumorigenesis. Importantly, targeting Hsp70, a protein folding chaperone translationally regulated by N-myc, suppressed tumor growth in mouse and human medulloblastoma xenograft models. These findings reveal a previously hidden molecular program that promotes medulloblastoma formation and identify new therapies that may have impact in the clinic. Significance: Translatome analysis in medulloblastoma shows that N-myc drives selective translation of transcripts that promote protein homeostasis and that represent new therapeutic vulnerabilities.
Inhaled Corticosteroids in Adults with Non-cystic Fibrosis Bronchiectasis: From Bench to Bedside. A Narrative Review
Authors: Miguel Ángel Martínez-García, Grace Oscullo, Alberto García-Ortega, Maria Gabriella Matera, Paola Rogliani, Mario Cazzola
Journal: Drugs (2022)

Due to their potent anti-inflammatory capacity (particularly in predominantly eosinophilic inflammation) and immunosuppressive properties, inhaled corticosteroids (ICSs) are widely used in asthmatic patients and also in individuals with chronic obstructive pulmonary disease (COPD) who suffer multiple exacerbations or have peripheral eosinophilia. However, there is little evidence for their use in non-cystic fibrosis bronchiectasis (hereafter, bronchiectasis). According to data extracted from large databases of bronchiectasis in adults, ICSs are used in more than 50% of patients without any scientific evidence to justify their efficacy and contrary to the recommendations of international guidelines on bronchiectasis that generally advise against their use. Indeed, bronchiectasis is a disease with predominantly neutrophilic inflammation and a high likelihood of chronic bacterial bronchial infection. Furthermore, it is known that due to their immunosuppressive properties, ICSs can induce an increase in bacterial infections. This manuscript aims to review the basic properties of ICSs, how they impact bronchiectasis in adults, the current position of international guidelines on this treatment, and the current indications and future challenges related to ICS use in bronchiectasis.
A Molecular Switch between Mammalian MLL Complexes Dictates Response to Menin–MLL Inhibition
Authors: Yadira M. Soto-Feliciano, Francisco J. Sánchez-Rivera, Florian Perner, Douglas W. Barrows, Edward R. Kastenhuber, Yu-Jui Ho, Thomas Carroll, Yijun Xiong, Disha Anand, Alexey A. Soshnev, Leah Gates, Mary Clare Beytagh, David Cheon, Shengqing Gu, X. Shirley Liu, Andrei V. Krivtsov, Maximiliano Meneses, Elisa de Stanchina, Richard M. Stone, Scott A. Armstrong, Scott W. Lowe, C. David Allis
Journal: Cancer Discovery (2022)

Abstract Menin interacts with oncogenic MLL1-fusion proteins, and small molecules that disrupt these associations are in clinical trials for leukemia treatment. By integrating chromatin-focused and genome-wide CRISPR screens with genetic, pharmacologic, and biochemical approaches, we discovered a conserved molecular switch between the MLL1–Menin and MLL3/4–UTX chromatin-modifying complexes that dictates response to Menin–MLL inhibitors. MLL1–Menin safeguards leukemia survival by impeding the binding of the MLL3/4–UTX complex at a subset of target gene promoters. Disrupting the Menin–MLL1 interaction triggers UTX-dependent transcriptional activation of a tumor-suppressive program that dictates therapeutic responses in murine and human leukemia. Therapeutic reactivation of this program using CDK4/6 inhibitors mitigates treatment resistance in leukemia cells that are insensitive to Menin inhibitors. These findings shed light on novel functions of evolutionarily conserved epigenetic mediators like MLL1–Menin and MLL3/4–UTX and are relevant to understand and target molecular pathways determining therapeutic responses in ongoing clinical trials. Significance: Menin–MLL inhibitors silence a canonical HOX- and MEIS1-dependent oncogenic gene expression program in leukemia. We discovered a parallel, noncanonical transcriptional program involving tumor suppressor genes that are repressed in Menin–MLL inhibitor–resistant leukemia cells but that can be reactivated upon combinatorial treatment with CDK4/6 inhibitors to augment therapy responses. This article is highlighted in the In This Issue feature, p. 1
Factors Associated With Severe COVID-19 Among Vaccinated Adults Treated in US Veterans Affairs Hospitals
Authors: Austin D. Vo, Jennifer La, Julie T.-Y. Wu, Judith M. Strymish, Matthew Ronan, Mary Brophy, Nhan V. Do, Westyn Branch-Elliman, Nathanael R. Fillmore, Paul A. Monach
Journal: JAMA Network Open (2022)

Importance With a large proportion of the US adult population vaccinated against SARS-CoV-2, it is important to identify who remains at risk of severe infection despite vaccination. Objective To characterize risk factors for severe COVID-19 disease in a vaccinated population. Design, Setting, and Participants This nationwide, retrospective cohort study included US veterans who received a SARS-CoV-2 vaccination series and later developed laboratory-confirmed SARS-CoV-2 infection and were treated at US Department of Veterans Affairs (VA) hospitals. Data were collected from December 15, 2020, through February 28, 2022. Exposures Demographic characteristics, comorbidities, immunocompromised status, and vaccination-related variables. Main Outcomes and Measures Development of severe vs nonsevere SARS-CoV-2 infection. Severe disease was defined as hospitalization within 14 days of a positive SARS-CoV-2 diagnostic test and either blood oxygen level of less than 94%, receipt of supplemental oxygen or dexamethasone, mechanical ventilation, or death within 28 days. Association between severe disease and exposures was estimated using logistic regression models. Results Among 110 760 patients with infections following vaccination (97 614 [88.1%] men, mean [SD] age at vaccination, 60.8 [15.3] years; 26 953 [24.3%] Black, 11 259 [10.2%] Hispanic, and 71 665 [64.7%] White), 10 612 (9.6%) had severe COVID-19. The strongest association with risk of severe disease after vaccination was age, which increased among patients aged 50 years or older with an adjusted odds ratio (aOR) of 1.42 (CI, 1.40-1.44) per 5-year increase in age, such that patients aged 80 years or older had an aOR of 16.58 (CI, 13.49-20.37) relative to patients aged 45 to 50 years. Immunocompromising conditions, including receipt of different classes of immunosuppressive medications (eg, leukocyte inhibitor: aOR, 2.80; 95% CI, 2.39-3.28) or cytotoxic chemotherapy (aOR, 2.71; CI, 2.27-3.24) prior to breakthrough infection, or leukemias or lymphomas (aOR, 1.87; CI, 1.61-2.17) and chronic conditions associated with end-organ disease, such as heart failure (aOR, 1.74; CI, 1.61-1.88), dementia (aOR, 2.01; CI, 1.83-2.20), and chronic kidney disease (aOR, 1.59; CI, 1.49-1.69), were also associated with increased risk. Receipt of an additional (ie, booster) dose of vaccine was associated with reduced odds of severe disease (aOR, 0.50; CI, 0.44-0.57). Conclusions and Relevance In this nationwide, retrospective cohort of predominantly male US Veterans, we identified risk factors associated with severe disease despite vaccination. Findings could be used to inform outreach efforts for booster vaccinations and to inform clinical decision-making about patients most likely to benefit from preexposure prophylaxis and antiviral therapy.
An overview of cdc2‐like kinase 1 (Clk1) inhibitors and their therapeutic indications
Authors: Ahmed K. ElHady, Dalia S. El‐Gamil, Ashraf H. Abadi, Mohammad Abdel‐Halim, Matthias Engel
Journal: Medicinal Research Reviews (2022)

Over the past decade, Clk1 has been identified as a promising target for the treatment of various diseases, in which deregulated alternative splicing plays a role. First small molecules targeting Clk1 are in clinical trials for the treatment of solid cancer, where variants of oncogenic proteins derived from alternative splicing promote tumor progression. Since many infectious pathogens hi-jack the host cell's splicing machinery to ensure efficient replication, further indications in this area are under investigation, such as Influenza A, HIV-1 virus, and Trypanosoma infections, and more will likely be discovered in the future. In addition, Clk1 was found to contribute to the progression of Alzheimer's disease through causing an imbalance of tau splicing products. Interestingly, homozygous Clk1 knockout mice showed a rather mild phenotype, opposed to what might be expected in view of the profound role of Clk1 in alternative splicing. A major drawback of most Clk1 inhibitors is their insufficient selectivity; in particular, Dyrk kinases and haspin were frequently identified as off-targets, besides the other Clk isoforms. Only few inhibitors were shown to be selective over Dyrk1A and haspin, whereas no Clk1 inhibitor so far achieved selectivity over the Clk4 isoform. In this review, we carefully compiled all Clk1 inhibitors from the scientific literature and summarized their structure-activity relationships (SAR). In addition, we critically discuss the available selectivity data and describe the inhibitor's efficacy in cellular models, if reported. Thus, we provide a comprehensive overview on the current state of Clk1 drug discovery and highlight the most promising chemotypes.
Viral infections and drug hypersensitivity
Authors: Werner J. Pichler, Marie‐Charlotte Brüggen
Journal: Allergy (2022)

Abstract Virus infections and T‐cell‐mediated drug hypersensitivity reactions (DHR) can influence each other. In most instances, systemic virus infections appear first. They may prime the reactivity to drugs in two ways: First, by virus‐induced second signals: certain drugs like β‐lactam antibiotics are haptens and covalently bind to various soluble and tissue proteins, thereby forming novel antigens. Under homeostatic conditions, these neo‐antigens do not induce an immune reaction, probably because co‐stimulation is missing. During a virus infection, the hapten‐modified peptides are presented in an immune‐stimulatory environment with co‐stimulation. A drug‐specific immune reaction may develop and manifest as exanthema. Second, by increased pharmacological interactions with immune receptors (p‐i) : drugs tend to bind to proteins and may even bind to immune receptors. Without viral infections, this low affine binding may be insufficient to elicit T‐cell activation. During a viral infection, immune receptors are more abundantly expressed and allow more interactions to occur. This increases the overall avidity of p‐i reactions and may even be sufficient for T‐cell activation and symptoms. There is a situation where the virus‐DHR sequence of events is inversed: in drug reaction with eosinophilia and systemic symptoms (DRESS), a severe DHR can precede reactivation and viremia of various herpes viruses. One could explain this phenomenon by the massive p‐i mediated immune stimulation during acute DRESS, which coincidentally activates many herpes virus‐specific T cells. Through p‐i stimulation, they develop a cytotoxic activity by killing herpes peptide‐expressing cells and releasing herpes viruses. These concepts could explain the often transient nature of DHR occurring during viral infections and the often asymptomatic herpes‐virus viraemia after DRESS.
Systemic Anticancer Therapy at the End of Life—Changes in Usage Pattern in the Immunotherapy Era
Authors: Maureen E. Canavan, Xiaoliang Wang, Mustafa S. Ascha, Rebecca A. Miksad, Gregory S. Calip, Cary P. Gross, Kerin B. Adelson
Journal: JAMA Oncology (2022)

This cohort study evaluates the rate of systemic anticancer therapy use among patients dying of cancer.
Genomic characterization reveals distinct mutation landscapes and therapeutic implications in neuroendocrine carcinomas of the gastrointestinal tract
Authors: Huanwen Wu, Zicheng Yu, Yueping Liu, Lei Guo, Lianghong Teng, Lingchuan Guo, Li Liang, Jing Wang, Jie Gao, Ruiyu Li, Ling Yang, Xiu Nie, Dan Su, Zhiyong Liang
Journal: Cancer Communications (2022)

Abstract Background Neuroendocrine carcinomas of the gastrointestinal tract (GI‐NECs) remain a disease of grim prognosis with limited therapeutic options. Their molecular characteristics are still undefined. This study aimed to explore the underlying genetic basis and heterogeneity of GI‐NECs. Methods Comprehensive genomic analysis using whole‐exome sequencing was performed on 143 formalin‐fixed, paraffin‐embedded samples of surgically resected GI‐NEC with a thorough histological evaluation. Mutational signatures, somatic mutations, and copy number aberrations were analyzed and compared across anatomic locations and histological subtypes. Survival analysis was conducted to identify the independent factors. Results In total, 143 GI‐NECs were examined: the stomach, 87 cases (60.8%); the esophagus, 29 cases (20.3%); the colorectum, 20 cases (14.0%); and the small intestine, 7 cases (4.9%). Eighty‐three (58.0%) and 60 (42.0%) cases were subclassified into small cell and large cell subtypes, respectively. GI‐NECs showed distinct genetic alterations from their lung counterparts and non‐neuroendocrine carcinomas in the same locations. Obvious heterogeneity of mutational signatures, somatic mutations, and copy number variations was revealed across anatomic locations rather than histological subtypes. Except for tumor protein p53 ( TP53 ) and retinoblastoma 1 ( RB1 ), the most frequently mutated genes in the stomach, esophagus, colorectum, and small intestine were low‐density lipoprotein receptor‐related protein 1B ( LRP1B ), notch receptor 1 ( NOTCH1 ), adenomatosis polyposis coli ( APC ), catenin beta 1 ( CTNNB1 ), respectively. Mutations in the WNT‐β‐catenin, NOTCH and erythroblastic leukemia viral oncogene B (ERBB) pathways were prevalently identified in gastric, esophageal, and colorectal NECs, respectively. Importantly, 104 (72.7%) GI‐NECs harbored putative clinically relevant alterations, and non‐gastric location and RB1 bi‐allelic inactivation with copy number alterations were identified as two independent poor prognostic factors. Furthermore, we found that tumor cells in GI‐NECs first gain clonal mutations in TP53 , RB1 , NOTCH1 and APC , followed by subsequent whole‐genome doubling (WGD) and post‐WGD clonal mutations in LRP1B , CUB and Sushi multiple domains 3 ( CSMD3 ), FAT tumor suppressor homolog 4 ( FAT4 ) and erb‐b2 receptor tyrosine kinase 4 ( ERBB4 ), and finally develop subclonal mutations. Conclusions GI‐NECs harbor distinct genomic landscapes and demonstrate significant genetic heterogeneity across different anatomic locations. Moreover, potentially actionable alterations and prognostic factors were revealed for GI‐NECs.
Methodologic Concerns in Secondary Analysis of KEYNOTE-048
Authors: Barbara Burtness, Jianxin Lin, Denis Souliéres
Journal: JAMA Oncology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal